INTRODUCTION:

Transdermal drug delivery system (TDDS) is an innovative, interesting, challenging area and alternative route for more traditional route like oral, intravascular, subcutaneous and transmucosal, for safer and effective medicinal delivery to the patients^1,5. It is a system in which the drugs are delivered through the skin to the systemic circulation painlessly by applying onto intact and healthy skin, by either passive or active means. Moreover in passive means drugs are delivered to systemic circulation without any physical disruption to the stratum corneum mainly by the principle of diffusion. In active means drugs are delivered to systemic circulation by utilising physical disruption of the stratum corneum or use of external driving force such as iontophoresis, sonication, magnetic field, microneedle etc.⁸

Methimazole an antithyhroid drug, it is available as conventional tablet dosage form in market of 5mg, 10 mg and 20 mg. Which is prescribed to be taken 3-4 times a day with usual treatment period of 16 – 18 weeks. It was choosen as a drug model for the present research work because it fullfills all the criteria needed for a successful transdermal dosage form to deliver the drug to a patient in effectively and safely and to overcome the limitation of oral methimazole treatment by eliminating multiple dose with single sustained released patch, by pass first pass metabolism, gastro irritability and with better patient compliance Following are the characteristics of the methimazole:^2,3

· It has a low molecular weight i.e 114.166g/mol.

· It has a melting low melting point of 146^◦C.

· It has a plasma half life of 4-6 hours.

· It undergoes rapid first pass metabolism thus required to taken frequently.

· It causes unwanted side effect with oral dosage form such as gastric irritation, loss of test, nausea and liver toxicity.

· It’s daily dosage maintenance is 5 to 15mg/day.

· The pH of the solution are practically a neutral to litmus.

The objective of this research work was to develop a transdermal matrix type patches of methimazole which can produce a constant and prolonged release of drug with mixture of hydrophilic polymer HPMC (Hydroxypropyl methyl cellulose) and hydrophobic polymer Ethyl Cellulose and Eudragit RL 100. And to perform the physiochemical characterization and invitro permeation studies to ensure sustained release of methimazole.

MATERIAL AND METHOD:

Material:

Methimazole was a gift sample from Innova Pharmaceuticals Pvt. Ltd., Nagpur, India. HPMC E-15, Eudragit RL 100 and ethylcellulose was purchased from SD. Fine Chem Ltd., PEG 400 and DBP was purchased from Quali Chem., New Delhi 11060, DMSO was purchased from SD. Fine Chem Ltd. Mumbai 400025. And all the other reagent used were of analytical Grade.

Formulation Design of Transdermal Patch

Calculation of total drug load:

Area of patch = 1 cm²

Desired drug concentration in small patch of 1cm²=10 mg

Area of petri Dish = 20.25cm²

Total amount of drug to be loaded = Area of petri × desired drug conc.

20.25 cm² × 10 mg

Area of small patch = -------------------------- = 202.5mg

1 cm²

Thus, 202.5mg of methimazole drug was added in each formulation to get a patch containing 10mg per small 1 cm².

Formulation of Methimazole matrix patch:

The matrix transdermal patch of methimazole was developed by solvent casting method using mixture of different polymers and in variable ratios (Table-1). Polymer and drug was accurately weight. Then firstly, the polymer was dissolved in the solvent and mix was for upto 10-15 minutes, then the required drug was added to the polymer solution and mix thoroughly with vortex shaker, to the mixture solution plasticizer (PEG 400 or DBP) and penetration enhancer (DMSO) were added and vortexed more for homogenous mixture. Then it was poured in the Petri dish which was previously lined with aluminium foil and dried at 80^◦C for 20 minutes in the hot oven.^10-13The dried patches were cut into small patches of 1 cm² and stored at desiccators for further study.

Drug Identification Test:

Physical characterization of drug:

For physical characteristic of drugs it was observed for appearance, odour and colour. It was recorded and was compared with the literature.

Melting point determination:

Melting point of drug Methimazole was determine by capillary fusion method using a melting point apparatus. Melting point was recorded and compared with literature value.

UV Spectrophotometric ( ℷ_max) study:

Methimazole (10mg) was weigh accurately and transferred to 100ml volumetric flask, it was dissolved and diluted to 100ml with ph 7.4 phosphate buffer to obtain 100µg/ml. From the first solution, dilution were made to obtain a final concentration of 5µg/ml and was scanned for ℷ_maxin a range of 200-400nm in the spectrum basic mode. ℷ_maxwere recorded and compared with literature value.^2,3

Preparation of calibration curve in ph 7.4 phosphate buffer:

Accurately 100mg of Methimazole was weight and was dissolved in 100ml of pH7.4 phosphate buffer to give a 1mg/ml, which gave the 1^st stock solution. From the 1^st stock solution 2ml was pippetted and transferred to 100 ml volumetric flask and volume was make up with pH 7.4 phosphate buffer upto 100ml to give 20µg/ml, 2^nd stock solution . Aliquot 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 ml from 2^nd stock solution and diluted upto 10ml with pH 7.4 phosphate buffer to give 1 to 10µg/ml respectively. The sample solution were then scanned at UV Spectrophotometer at 252nm and absorbance were recorded, and graph was plotted between absorbance and concentration to obtain a calibration curved.⁶

Table. 1. Composition and Formulation of transdermal patch:

Sl. No	Ingredient	F1	F2	F3	F4	F5	F6	F7	F8	F9
1.	Drug	202.5	202.5	202.5	202.5	202.5	202.5	202.5	202.5	202.5
2.	HPMC E-15 (mg)	250	125	125	75	75	-	-	-	-
3.	Ethyl cellulose (mg)	-	125	-	175	-	250	125	75	-
4.	Eudragit RL 100 (mg)	-	-	125	-	175	-	125	175	250
5.	Dibuthyl phthalate (ml)	0.15	0.15	-	.15	-	0.15	-	-	-
6.	PEG 400 (ml)	-	-	0.15	-	0.15	-	0.15	0.15	0.15
7.	DMSO	0.15	0.15	0.15	0.15	0.15	0.15	0.15	0.15	0.15
8.	Ethanol (ml)	3	3	3	3	3	3	3	3	3

Characterization and evaluation of transdermal patch:

Weight uniformity test:

A specific area of the patches was cut carefully in different parts and afterwards weighted in a digital balance. The average weight and standard deviation values were calculated from the individual weight.^6-8

Thickness uniformity of patches test:

The thickness of the patches was determined by vernier calibre at different places and mean values are calculated and noted.⁹

Folding endurance test:

A patch on specific area was cut evenly and repeatedly folded at the same place until it was broken. Number of times the film could be folded at the same place without breaking gave the value of folding endurance.^12,14

Drug content test:

An area of 1cm² of patch was cut and dissolved in 2ml of ethanol and volume was made up to 10ml with 7.4 ph phosphate buffer. Filtered was then scanned in UV spectrophotometer at wavelength of 252nm.¹¹

Percent moisture contained:

The prepared transdermal patch were weighed and kept in the dissicators containing fused calcium chloride at room temperature for the duration of 24 hours. After 24 hours the patch were re-weighed and the percent moisture contained was determined by the formula:^12-14

Initial weight – Final weight

Percent moisture = ------------------------------------- × 100

content Final weight.

Percentage moisture uptake:

The prepared transdermal patch were weighed films kept in a desicator at room temperature for 24 hrs. These are then taken out and exposed to 84% relative humidity using saturated solution of potassium chloride in a desicator until a constant weight is achieved. Percentage moisture uptake was calculated as given below.^7-9

Final weight- Initial weight

% Moisture uptake = ---------------------------------- X 100

Initial weight

In-Vitro Drug Release Study:

Invitro release of methimazole from prepared matrix patch was studied using Franz Diffusion cell using an egg shell membrane. The diffusion medium used for study was phosphate buffer saline solution of pH 7.4. The drug containing film with a supporting backing membrane was kept in a donor compartment. The donor and receptor chamber was hold together using a spring of strong grip. The temperature of dissolution medium in receptor chamber was maintained at 32±5^◦C. the diffusion medium was stirred with magnetic bar to prevent the formation of concentrated drug solution layer below the standard membrane. The amount of drug permeated into the receptor solution was determined by removing 1ml of sample at fixed interval upto 12 hours. The samples were then scanned in UV spectrophotometer at wavelength of 252nm.^9,11,15

RESULT AND DISCUSSION:

Drug identification tests:

Physical characterization of drug:

For the organoleptic test the Methimazole drug was solid, white to pale buff starch like in appearance to touch, which complies with the description given in the literature. (USP) (Table 2)

Melting point Determination:

Melting point of Methimazole was found 146^◦C which complies with the literature value of 146^◦C indicating the purity and confirmation of drug sample (USP). (Table 2)

UV Spectrophotometry:

UV Spectrophotometry study was carried out for the λmax value of the Methimazole in the phosphate buffer pH 7.4. The standard stock solution was prepared for the given drug and scanned under UV spectrophotometer in the wavelength range of 400-200nm against the blank solution. The λmax of the Methimazole was found 252 nm which is matched with reported UV spectrum of Methimazole in literature, which indicates the purity and confirmation of the drug sample. As shown in Table 2.

Calibration curve of Methimazole in Phosphate buffer of pH 7.4:

Methimazole Calibration curve was made in the phosphate buffer pH7.4. Methimazole sample solution concentration range in phosphate buffer pH 7.4 was 1-10 μg/ml and was scanned under UV spectrophotometer at 252nm. Calibration curve was plotted between the absorbance Vs concentration of dilution. The data were plotted without standard deviation and the calibration curve (Fig.1) obtained followed Beer’s- Lambert law with regression coefficient (r2) value of 0.9991 in phosphate buffer pH 7.4. The regression equations is Y= 0.0149 x

Table 2 Drug identification test

Sl. No.	Parameter	observation	Reported
1.	Physical description	solid	solid
2.	Colour	White to pale buff	White to pale buff
3.	Melting point	146 ^◦C	146 -148 ^◦C
4.	λmax	252 nm	252nm

Fig 1: calibration curve of Methimazole

Evaluation of transdermal patch:

Weight uniformity:

A specific area of the patches was cut carefully in different parts and afterwards weighted in a digital balance. It was found that the weight varied from (39.12±.91mg to 41.25±.62mg) and the values lies within the limit range. Thus these uniformity in weight assure that the procedure is reproducible and which will give uniform distribution of drug as well. (Table 3)

Thickness of patches:

The thickness of the patches varied from 0.3±3.41mm to 0.5±6.16mm. The minimum standard deviation values assured that the process used for preparing the delivery system is capable of giving reproducible results. (Table 3)

Folding endurance:

The folding endurance was measured manually; films were abled to be folded without crack for between 76 to 98 and if folded shows any cracks it was taken as end point. All the patches indicates good strength and elasticity. (Table 3)

Drug content:

Study of uniformity of drug content is important to ensure the reproducibility, efficacy and safety of formulation dosage form. From the study it showed that all the patches has a satisfactory drug content which has a value from 96.7 to 99.8 % which was found to be satisfactory. (Table 3)

Percent moisture contained:

Moisture contained of patches were determines and was found that the patches from F1to F9 has a moisture contained from 1.3 to 2.5 %. The percent moisture content of the patches is important as it will determine the stability of the drug and patches. It was found that patches with higher ratio of hydrophilic polymer has greater moisture content than the patches with only hydrophobic polymer.(Table 3)

Percent moisture uptake:

Study of moisture uptake is an important study to determine the stability of the patches on storage of their shelf life. From the study it is showed that the patches with higher hydrophilic polymer concentration showed higher moisture uptake as compared with higher hydrophobic concentration. The moisture uptake of patches of F1 to F9 ranges from 5.2 to 9.72 %.(Table 3)

Table 3: Evaluation of Prepared Methimazole Transdermal Patch

Formulation code	Weight uniformity (mg)	Thickness (mm)	Folding endurance	Drug content (%)	% Moisture content	% Moisture uptake
F1	40.3± .8	0.4± 4.21	≥98	99.8± 0.69	2.5±1.8	9.7±2.14
F2	40.6± .76	0.3± 3.58	≥82	98.6±0.36	1.3±1.3	7.3±2.8
F3	41.2±.89	0.3 ± 6.3	≥79	98.2±0.54	2.1±1.6	7.1±1.69
F4	40.5±.24	0.5± 6.16	≥86	97.9±0.52	1.6±0.6	8.7±1.63
F5	40.6 ±.82	0.4 ± 8.4	≥90	98.6±0.27	1.8±1.3	8.2±2.4
F6	39.12± .91	0.3 ± 3.41	≥74	97.1±0.85	1.6±1.4	5.2±3.1
F7	40.78± .64	0.5 ± 4.17	≥76	96.7±0.77	1.4±0.5	5.8±2.96
F8	40.50 ±.41	0.4 ± 6.2	≥81	99.2±0.64	1.5±0.6	7.3±1.21
F9	40.33±.56	0.4 ± 7.2	≥83	98.1±0.87	1.6±1.2	7.6±2.48

Fig 2 Drug content % of different Formulation

In-Vitro Released Study:

In-vitro drug release study was done using a Franz diffusion cell, using an eggshell membrane. Content of the egg was first emptied and washed with water, then the empty shell was introduced to a concentrated HCl so to dissolve the outer calcified covering, leaving behind the shell membrane which was used for the study.

The formulated medicated patches were subjected to in-vitro release study for 12 hours, the CDR% and the Release kinetics of all the formulation (F1- F9) is given in the Table 4 and Table 5 respectively. From the result we see that formulation F1 showed a maximum release of the drug upto 83.45 and the formulation F6 showed the least release of drug i.e 63.87 %. The diffusion rate was scrutinized as F1˃F5˃F4˃F2˃F9˃F3˃F8˃F7˃F6. The release pattern from the patch were affected by the nature of the polymer and the concentration ratio of the polymers. The patches formulated with the hydrophilic polymer and its mixture showed to release more (F1, F2, F3, F4 and F5) as compared with the patches formulated with hydrophobic polymers, the formulation with Eudragit RL 100 showed a more release F9˃F8˃F7˃F6 than with ethyl cellose, the reason may be because Eu RL 100 has a high water permeability characteristics. Therefore the optimisation is very important in the formulating a patch to release the drug in predetermined manner and in maximum. The release pattern of the drug from the patch also depends on the affinity of the drug to the nature of the polymer. The CDR% of all formulation were subjected to a Bit-soft software to determine the release kinetic of drug from the patch. From result F1 and F3 follows Peppas kinetics, F2 and F6 follows first order kinetics, F8 followed Hixon crowel model and F4, F5, F7 and F9 follows a zero order kinetics, which is ideal for the transdermal delivery system. From these formulation F5 was chosen as the best formulation because this optimised formulation showed satisfactory drug content, physical characteristic for its thickness, weight uniformity, percentage moisture content, percentage moisture uptake, and maximum release upto 81.12 in 12 hour and followed a zero order kinetic release pattern.

Table 4: in-vitro drug Release study in Franz Diffusion cell

Time	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
30 Min	5.25	4.2	4	6	5.33	3.58	4.25	5.1	3.98
1hr	12.47	13.44	11.02	11.3	12.77	15.24	15.25	11.09	10.96
2 hr	20.48	21.96	17.66	19.01	16.25	36.14	16.17	17.96	16.32
3 hr	28.14	32.11	23.14	25.32	23.01	31.92	21.45	24.8	21.17
4 hr	33.15	40.26	29.47	31.36	28.37	38.21	25.84	30.21	27.21
5 hr	41.86	47.36	35.41	38.21	36.87	44.15	31.47	37.01	33.5
6 hr	49.89	54.18	42.34	43.11	42.17	50.19	36.49	43.8	40.85
7 hr	58.14	62.14	48.78	50.34	49.99	53.12	41.7	48.02	47.24
8 hr	67.36	66.15	55.71	56.1	58.24	54.28	46.21	55.9	53.14
9 hr	73.69	72.01	61.28	63.21	65.771	58.99	51.87	61.2	60.75
10 hr	78.14	75.31	68.24	72.14	76.281	60.22	59.36	66.2	68.24
12 hr	83.45	78.45	72.66	78.83	81.12	63.87	68.4	72.05	76.25

Table 5: Release kinetics data of Methimazole Patch with their R²value and best fitting model

F. Code	Zero order	1^storder	Higuchi matrix	Peppas	Hixon crowell	Best fitting model
F1	0.9851	0.9768	0.9272	0.9957	0.9904	Peppas
F2	0.9604	0.9968	0.9335	0.9934	0.9931	1^st order
F3	0.9901	0.9855	0.9256	0.9975	0.9937	Peppas
F4	0.9938	0.9678	0.9214	0.9907	0.9872	Zero order
F5	0.9918	0.9468	0.9203	0.9843	0.9726	Zero order
F6	0.9.35	0.9653	0.9368	0.9567	0.9478	1^storder
F7	0.9948	0.9758	0.9181	0.9943	0.9888	Zero order
F8	0.9881	0.9920	0.9260	0.9958	0.9971	Hixon crowell
F9	0.9965	0.9669	0.9228	0.9923	0.9855	Zero order

Fig 3 Release kinetics for formulation F5.

DISCUSSION:

The aim of this research study was to formulate a controlled and sustained release transdermal matrix type patch of Methimazole, to overcome the limitation of oral methimazole treatment by eliminating multiple dose with single sustained released patch, by pass first pass metabolism, gastro irritability and with better patient compliance.

The transdermal matrix patch of Methimazole was developed using various polymers in different mixture concentration i.e 100:0, 50:50, 30:70 ratio of HPMC (Hydrophilic polymer), Eudragit RL 100 and Ethyl Cellulose (Hydrophobic polymer). The formulations were subjected for various physiochemical and characteristic test and in-vitro drug release test using Franz Diffusion cell and the results were all under acceptable range. In the weight uniformity test all the formulation showed a uniformity within its average standard range, in thickness test also all the formulation showed a uniformity in its thickness which showed that reproducibility of the patch with this technique. Also the result for the moisture uptake and moisture content of the formulations showed that the moisture uptake and moisture content it depends on the nature of the polymer used for the preparation of patches, the patches with higher ratio of hydrophilic polymer showed a higher moisture content as compare to the patches prepared using hydrophobic polymer. In-vitro release of drug from the patch also depends on the nature of polymer used for formulation as such that the patch formulated with the hydrophilic polymer and its mixture showed to release more (F1, F2, F3, F4 and F5) as compared with the patches formulated with hydrophobic polymers, the formulation with Eudragit RL 100 showed a more release F9˃F8˃F7˃F6 than with ethyl cellose, the reason be because Eu RL 100 has a high water permeability characteristics. The result of the study also showed that the choice of polymer and excipients plays a crucial role for developing a good medicated patch for i.e the plasticizer PEG 400 was a good plasticizer for Euragit RL100 and HPMC patch but it gives brittle whereas plasticizer DBP was a good plasticizer for EC and HPMC but gives a brittle patch with Eudragit RL 100. From the all formulation F5 was chosen as a best Formulation, because this optimised formulation showed satisfactory drug content, physical characteristic for its thickness, weight uniformity, percentage moisture content, percentage moisture uptake, and maximum release upto 81.12 in 12 hour and followed a zero order kinetic release pattern.

CONCLUSION:

The prototype transdermal patches of Methimazole were prepared successfully using polymers- HPMC, Ethylcellulose and Eudragit RL 100. From the Physicochemical characteristics and in vitro drug release results F5 (HPMC: Eu RL 100) (30:70) was chosen as a best formulation among total nine formulation. Therefore the results of the study encourages a further study and are hopeful that the present study would contribute to the recent Pharmaceutical research activity.

ACKNOWLEDGEMENT:

Authors are thankful to Innova Pharmaceuticals Pvt. Ltd., Nagpur, India for giving the gift sample of methimazole and also thankful to Rajiv Academy for Pharmacy for providing necessary facilities for performing.

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Received on 29.07.2020 Modified on 08.09.2020

Research J. Pharm. and Tech. 2021; 14(9):4667-4672.

DOI: 10.52711/0974-360X.2021.00811